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Discovery of 2,6-Dimethylpiperazines as Allosteric Inhibitors of CPS1.

ABSTRACT: Carbamoyl phosphate synthetase 1 (CPS1) is a potential synthetic lethal target in LKB1-deficient nonsmall cell lung cancer, where its overexpression supports the production of pyrimidine synthesis. In other cancer types, CPS1 overexpression and activity may prevent the accumulation of toxic levels of intratumoral ammonia to support tumor growth. Herein we report the discovery of a novel series of potent and selective small-molecule inhibitors of CPS1. Piperazine 2 was initially identified as a promising CPS1 inhibitor through a high-throughput screening effort. Subsequent structure-activity relationship optimization and structure-based drug design led to the discovery of piperazine H3B-616 (25), a potent allosteric inhibitor of CPS1 (IC₅₀ = 66 nM).

SUBMITTER: Rolfe A

PROVIDER: S-EPMC7294722 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Discovery of 2,6-Dimethylpiperazines as Allosteric Inhibitors of CPS1.

Rolfe Alan A Yao Shihua S Nguyen Toung-Vi TV Omoto Kiyoyuki K Colombo Federico F Virrankoski Milena M Vaillancourt Frédéric H FH Yu Lihua L Cook Andrew A Reynolds Dominic D Ioannidis Stephanos S Zhu Ping P Larsen Nicholas A NA Bolduc David M DM

ACS medicinal chemistry letters 20200526 6

Carbamoyl phosphate synthetase 1 (CPS1) is a potential synthetic lethal target in LKB1-deficient nonsmall cell lung cancer, where its overexpression supports the production of pyrimidine synthesis. In other cancer types, CPS1 overexpression and activity may prevent the accumulation of toxic levels of intratumoral ammonia to support tumor growth. Herein we report the discovery of a novel series of potent and selective small-molecule inhibitors of CPS1. Piperazine <b>2</b> was initially identified ...[more]

PMID: 32551016

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